The present invention is directed to cyclohexenyl-substituted thiourea compounds useful in providing contraceptive, e.g. spermicidal, effects. In one particular embodiment, the present invention is directed to novel dual-function cyclohexenyl-substitued thiourea compounds that exhibit both spermicidal activity and potent anti-microbial, particularly anti-viral, activity.
Human immunodeficiency virus (HIV), the etiologic agent of acquired immunodeficiency syndrome (AIDS) is the fastest growing cause of death in women of reproductive age [1-31]. Worldwide, heterosexual transmission accounts for 90% of all HIV infections in women [2, 4]. Currently an estimated 14.1 million women worldwide are infected with HIV, representing 44% of all adult infections. Considering that the AIDS pandemic is still in its infancy on a global scale, this evolving demographic situation warrants urgent attention particularly for the adolescent population. Therefore, effective strategies are needed to reduce heterosexual and perinatal HIV transmission. In the absence of an effective prophylactic anti-HIV therapy or vaccine, new emphasis has been placed on the development of intravaginal microbicidal agents capable of reducing the transmission of HIV [5, 6]. In addition, prophylactic contraception is fundamentally important in HIV-infected women for prevention of HIV transmission and pregnancy, especially because 80% of women with AIDS are of childbearing age [7].
At present, all commercially available spermicidal microbicides have detergent ingredients that disrupt cell membranes [8, 9]. The most widely used vaginal spermicide, nonoxynol-9 (N-9), because of its membrane disruptive properties has been shown to damage the cervicovaginal epithelium [10-12], cause an acute inflammatory tissue response [13], alter vaginal microflora [14, 15], and enhance the risk of promoting opportunistic infections in the genitourinary tract [16]. Such opportunistic infections are known to enhance the susceptibility of the ectocervical epithelium and the endocervical mucosa to HIV infection [17-19]. Despite its ability to inactivate HIV in vitro, the reported failure of N-9 to prevent heterosexual vaginal transmission of HIV in clinical settings in addition to its adverse effects on the cervicovaginal epithelium and vaginal microflora has prompted the search for new female-controlled microbicides that are both more effective and safer than N-9 [20-24]. Unlike the detergent-based microbicides that target cell membranes, the intravaginal or intrarectal use of topical formulations of anti-HIV drugs such as non-nucleoside inhibitors (NNIs) might be an effective approach for preventing the sexual transmission of HIV. These inhibitors of viral replication have been proposed by the WHO as candidates for intravaginal microbicides to inhibit HIV replication in mucosal cells [25, 26]. Inasmuch as physiological fertilization is dependent on the ability of ejaculated sperm to swim, bind the zona pellucida, and penetrate the egg, that are primarily dependent on sperm motility, adding spermicidal function to potent anti-HIV drugs could be an effective way to curb heterosexual HIV transmission as well as prevent conception.
Design of potent inhibitors of HIV-1 reverse transcriptase (RT) has been a focal point in translational AIDS research [27-30]. The NNIs are a diverse set of compounds which include tetrahydroimidazobenzodiazepinethione (TIBO) compounds [31], 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) derivatives [32-35], bis(heteroaryl)piperazine (BHAP) analogs[30], 2xe2x80x2-5xe2x80x2-bis-O-(tertbutyldimethylsilyl)-3xe2x80x2-spiro-5xe2x80x3-(4xe2x80x3-amino-1xe2x80x3, 2xe2x80x3-oxathiole-2xe2x80x3, 2xe2x80x3-dioxide) pyrimidine (TSAO) [36], dihydroalkoxybenzyloxopyrimidine (DABO) [37, 38], and phenethylthiazolylthiourea (PETT) derivatives [39-42]. These NNIs interfere with the activity of viral RT by binding to a specific allosteric site of HIV-1 RT near the polymerase site and severely limit the conformational flexibility needed for RT function, rendering the viral protein inactive [43-49]. A number of crystal structures of RT complexed with NNIs have been reported, and such structural information has provided the basis for further derivatization of NNI aimed at maximizing binding affinity to RT [44-50].
The success of NNIs for the clinical treatment of AIDS has led us to the computer-aided design and chemical synthesis of mechanism-based anti-retroviral agents that also exhibit spermicidal activity. Recently, we described structure-based design and synthesis of novel NNIs by generating a novel computer model in which a composite binding pocket was constructed from 9 individual crystal structures of RT-NNIs complexes [51, 52]. This computer docking procedure revealed abundant sterically allowed usable space surrounding the pyridyl ring of the thiourea compound, trovirdine. Using this model, we strategically designed novel compounds having functional groups that better fit and interact in the binding pocket space, to obtain more potent anti-HIV agents with higher affinity for the NNI binding pocket of HIV-1 RT that also exhibit spermicidal activity [53]. Continued development of novel agents designed to utilize the spatial and chemical relationships defined in the RT-NNI binding pocket model is needed to obtain alternative potent anti-microbial agents, and preferably, dual-function microbicides exhibiting spermicidal activity.
The present invention provides novel thiourea compounds that are useful as anti-microbial, e.g., anti-viral, and contraceptive agents, as well as products and methods using these compounds. Examples of such useful products include vaginal foams, creams, lotions or gels, sponges or other vaginal inserts, and condom lubricating compositions. The present invention also is directed to certain thiourea compounds that exhibit contraceptive properties while maintaining activity against microorganisms, such as HIV.
Particularly useful compounds of the invention are cyclohexenyl-substituted thioureas as described more fully below. Specific cyclohexenyl ring-containing thiourea compounds are identified in the Examples below as preferred, potent, dual-function anti-microbial and spermicidal agents. In particular, PHI-346 (N-[2-(5-bromopyridinyl)]-Nxe2x80x2-[2-(1-cyclohexenyl)ethyl]-thiourea); and PHI-445 (N-[2-(5-chloropyridinyl)]-Nxe2x80x2-[2-cyclohexenyl)ethyl-thiourea), were identified as most preferred dual-function anti-HIV spermicides.
The present invention also provides contraceptive products that utilize the dual function spermicidal thiourea compounds of the invention, preferably substituted cyclohexenyl thiourea compounds, as active agents, and to the production of such contraceptive products.
Methods of the invention include the step of contacting sperm with a spermicidal thiourea compound of the invention, for example by means of a contraceptive product of this invention as discussed above.